Arsene Wenger's men go into the game at the top of the group but know that a heavy defeat, coupled with a win for Dortmund, could see them exit the tournament.
Arsene Wenger's men currently sit top of Group F, three points clear of second-placed Borussia Dortmund and third-placed Napoli, and would secure a place in the last 16 with a draw at the Stadio San Paolo.
A draw would also be enough for Napoli if Dortmund loses at Marseille - which has yet to register a single point in the competition - and Arsenal could yet be eliminated from the competition, despite its strong position going into matchday six.
Should Napoli beat Wenger's side by three goals or more and Dortmund triumph over Marseille, the three sides will be tied on 12 points, meaning goal difference from matches played between the trio will be taken into account and leaving Arsenal at the bottom of the three.
The Premier League leader recorded a comfortable 2-0 victory over its Serie A opponent in the reverse fixture at the Emirates Stadium on Oct. 1, with Mesut Ozil and Olivier Giroud netting.
However, Napoli has won both of its home Champions League fixtures this term, beating Dortmund 2-1 and Marseille 3-2.
The Italians have earned a reputation for their strong home form domestically too, having gone 16 Serie A games unbeaten until Parma won 1-0 at the San Paolo on Nov. 23.
Arsenal has qualified for the knockout stages 13 seasons in a row, but will need to improve on the 4-0 defeat suffered on its last trip to Italy in this competition when AC Milan beat the club in Feb. 2012.
Wenger could do with Jack Wilshere finding his quick-fire shooting boots again, after the 21-year-old scored the fastest Champions League goal ever by an Englishman against Marseille on matchday five, finding the net in just 29.56 seconds.
Arsenal's last domestic outing saw it draw 1-1 with Everton on Sunday, and Wenger recently criticized his side's schedule that sees the club travel to Manchester City just three days after its visit to Naples.
"It is massively demanding because we have big games and, mentally as well, we want to be at a level to concentrate every time we turn up, with the top level of commitment," the Frenchman said. "That is a big challenge for us."
Bacary Sagna (hamstring) and Lukas Podolski (hamstring) remain doubtful for Arsenal, while Alex Oxlade-Chamberlain (knee) is unlikely to return to action until the new year.
Napoli, meanwhile, is likely to be without Marek Hamsik (foot) and long-term absentees Camilo Zuniga and Giandomenico Mesto (both knee).